The α11 integrin mediates fibroblast–extracellular matrix–cardiomyocyte interactions in health and disease

Excessive cardiac interstitial fibrosis impairs normal cardiac function. We have shown that the α11β1 (α11) integrin mediates fibrotic responses to glycated collagen in rat myocardium by a pathway involving transforming growth factor-β. Little is known of the role of the α11 integrin in the developing mammalian heart. Therefore, we examined the impact of deletion of the α11 integrin in wild type mice, and in mice treated with streptozotocin (STZ), to elucidate the role of the α11 integrin in normal cardiac homeostasis and in the pathogenesis of diabetes related fibrosis. As anticipated, cardiac fibrosis was reduced in α11 integrin knockout mice (α11(-/-); C57BL/6 background) treated with STZ compared with STZ-treated wild type mice (P < 0.05). Unexpectedly, diastolic function was impaired in both vehicle and STZ-treated α11(-/-) mice as shown by decreased dP/dtmin and prolonged Tau, in association with increased end-diastolic pressure (all P < 0.05 c/w wild type mice). Accordingly, we examined the phenotype of untreated α11(-/-) mice. α11(-/-) mice demonstrated reduced cardiomyocyte cross-sectional cell area and myofibril thickness (all P < 0.05 c/w wild type mice) and impaired myofibril arrangement. Immunostaining for desmin and connexin 43 showed abnormal intermediate filament organization at intercalated disks and impaired gap junction development. Overall, deletion of the α11 integrin attenuates cardiac fibrosis in the mammalian mouse heart and reduces extracellular matrix formation as a result of diabetes. Furthermore, α11 integrin deletion impairs cardiac function and alters cardiomyocyte morphology. These findings shed further light on the poorly understood interaction between the fibroblast-cardiomyocyte and the extracellular matrix.